Tick bite on a shoulder with central black spot
Skin erythema migrans
Systemic symptoms of malaise, fatigue, headache, and joint or muscle pain are associated with EM in half of all patients .
Borrelial lymphocytoma and acrodermatitis atrophicans are other manifestations of LD, the skin being the most affected body tissue [18–23].
Nervous System Early neuroborreliosis symptoms are related to protracted aseptic meningitis (transient or persistent headache) and cranial nerve (mainly facial nerve with transient facial palsy) or peripheral nerve involvement (pain as a result of radiculoneuritis) [24, 25].
Cerebrospinal fluid (CSF) examination shows lymphocytic pleocytosis.
One tenth of European patients show disseminated encephalomyelitis symptoms resembling multiple sclerosis, whereas American-affected subjects more frequently report signs of encephalopathy (neuropsychiatric features) [26–33].
Heart Changing atrioventricular blocks as a result of conduction disturbances and arrhythmias are frequent but usually transient. If they persist, they can lead to chronic cardiomyopathy [34–41].
Joints Intermittent attacks of asymmetrical inflammation of one or more joints are typical of Lyme arthritis. The mono-/oligoarticular form is more frequent in American patients. 10 % of patients have long-standing arthritis with longer than 1-year duration. Increase of ESR and IgM, leukocytosis, and the presence of circulating immune complexes (CIC) and cryoglobulins are not specific serologic inflammatory features. Synovial fluid examination shows increased presence of polymorphonuclear leukocytes [42–44].
5.1.4 Stages of Lyme Disease
Untreated LD clinical manifestations occur in three stages:
1st stage corresponds to erythema migrans skin rash which appears 3–30 days after the tick bite.
2nd stage is related to multi-organ involvement with neurologic, cardiac, joint inflammatory involvement which appears weeks to months after the tick bite.
5.2 Ocular Manifestations
In animal model studies, it was shown that Borrelia invades the eye very early after infection but may remain quiescent for a long time [47–50].
Several eye inflammatory signs and symptoms can appear, some months after the onset of systemic Lyme disease, and ocular chronic late manifestations are usually associated with other expressions of the disease such as arthritis .
Eyes can be affected: primarily as a result of the direct involvement of the ocular tissues (conjunctivitis, episcleritis, scleritis, or keratitis are the main signs, followed by anterior uveitis, retinal vasculitis, retinochoroiditis, and optic nerve inflammation, rarely panuveitis) or secondarily as a result of systemic manifestations (orbital myositis and palsies of cranial nerves) [50–53].
Severe photophobia, color vision disorders, or visual hallucinations and periocular pain are symptoms frequently reported by patients affected by corneal or neuro-ophthalmic involvement.
Blurred vision, floaters, and worsening of visual acuity are typical symptoms of vitreoretinal inflammatory involvement [60, 61].
During the flu-like illness of LD, a nonspecific follicular conjunctivitis may occur in 1/10 of patients, and it is frequently associated with lid or conjunctival chemosis and/or episcleritis. A patient – even if a child – with any of these manifestations should be questioned as to endemic area, tick bite, skin rash, and arthritis and should undergo serological testing [62, 63]. Children and people living or working in rural endemic areas are the most exposed.
Early-stage manifestations The first sign of ocular involvement is follicular conjunctivitis related to flu-like illness symptoms, followed some weeks later by nummular keratitis . Superficial and interstitial keratitis can be localized in the limbus area and can produce corneal limbus ulcers (Fig. 5.3). Exposure keratitis related to the seventh peripheral nerve palsy is also described [64–66].
360° borrelial limbal keratitis
Borrelia-associated crystalline keratopathy is a rare reported manifestation .
Late-stage manifestations Episcleritis  (Fig. 5.4), iritis, anterior uveitis, vitritis (with “spider’s web” aspect), intermediate uveitis, and posterior involvement occur infrequently and usually appear in the late stages [69–71].
Episcleritis and limbal keratitis
Uveitis is usually a late finding, and anterior uveitis is frequently associated with papillitis. It is characterized by granulomatous keratic precipitates or various degrees of flare and cells (Fig. 5.5); sometimes, posterior synechiae (usually in the inferior part of the iris) and iris nodules may be present [72, 73].
Lyme disease typical granulomatous uveitis
Intermediate uveitis typically affects children and presents as hyalitis and granulomatous vitritis ranging from traces to 4+ and spider’s web aspect [60, 74] (Fig. 5.6).
Spider’s web characteristic Lyme vitreous inflammation
Vitreous snowballs typically are yellow-white inflammatory aggregates and are found in the mid vitreous and inferior periphery. Snowbanks are exudates on the pars plana which, when present, are usually found inferiorly, but may also extend all around the retinal periphery; this finding is usually associated with severe forms of the disease and needs aggressive therapy  (Fig. 5.7). Retinal changes are represented by arteriolar winding and vascular sheathing mainly of peripheral veins, neovascularization, and retinal detachment [74, 75].
Intermediate uveitis in a Lyme-affected child (7 years old) with a 360° snowbank at the level of the pars plana
Posterior uveitis may show (1) a serous posterior pole detachment (if bilateral, it is difficult to distinguish from Vogt-Koyanagi-Harada syndrome) (Figs. 5.8, 5.9, 5.10, 5.11, and 5.12), (2) a peripheral multifocal choroiditis with an aspect similar to that of sarcoidosis (Figs. 5.13 and 5.14), and/or (3) cotton wool spots, typically followed by recurrent episodes of anterior uveitis [76, 77]. A distinct clinical entity related to LD posterior pole involvement is peripheral multifocal choroiditis with multiple small retinal lesions associated with intraocular inflammation [78, 79].
Borrelial unilateral papillitis
Red-free retinography. Unilateral acute papillitis
Fluorescein angiography (FA) early angiogram of Lyme unilateral acute papillitis
FA late angiogram of unilateral acute papillitis showing intense leakage from the optic nerve
FA shows full recovery after 1-month systemic therapy
FA shows RE posterior pole inflammatory serous detachment
FA shows LE papillitis (in the same patient)
Retinal vasculitis is actually more frequent than in previous reports (Fig. 5.15) and involves both the arterial and the venous system and may result in vascular occlusion [61, 80, 81]. Occlusive vasculitis, mainly of retinal veins, has a similar appearance to syphilitic retinal vasculitis.
Peripheral multifocal choroiditis resembling sarcoidosis
Panuveitis is rare but a blinding disease .
Fluorescein angiography in cases of neuroretinitis may show retinal edema and areas of cystoid patchy and peripapillary hyperfluorescence in the macula and peripapillary area; it shows also focal leakage as a sign of retinal vasculitis which can affect either veins or arteries [72, 78, 82] (Fig. 5.16 and Figs. 5.17, 5.18, 5.19, 5.20, 5.21, and 5.22).
FA late angiograms showing diffuse borrelial retinal vasculitis and cystoid macular edema
RE autofluorescence patchy area at the posterior pole of RPE inflammation and mottled pigment
RE FA epithelitis and mottled pigment
RE ICG-A patchy area at the posterior pole of RPE inflammation or hypoperfusion
LE autofluorescence showing the same aspect of RE
RE FA epithelitis and mottled pigment
RE ICG-A patchy area at the posterior pole of RPE inflammation or hypoperfusion
5.3 Neuro-ophthalmological Manifestations
Neuro-ophthalmological manifestations belong to the early stages of the disease probably due to the Borrelia blood-brain barrier passage and include multiple cranial nerve involvement (Bell’s palsy), optic disc edema both inflammatory and intracranial hypertension derived, late optic atrophy, and neuroretinitis [83, 84]. Sometimes orbital involvement with myositis begins with diplopia mimicking neurological involvement .
Optic neuropathy is rare and is characterized by painless visual loss, unilateral or bilateral optic nerve head swelling, and ischemic optic neuropathy [86–88] (Fig. 5.23). If appearing as the first sign of the disease, it might be indistinguishable from the first neuritic attack of multiple sclerosis [89, 90].
FA showing Lyme disease typical retinal sectorial vasculitis
5.4 Diagnostic Investigations
LD diagnosis is difficult, and it is mainly based on medical history, physical examination, and Lyme infection serological tests. Ideally, detection of the causative agent via culture or PCR from infected tissues, blood, and synovial or cerebrospinal fluid should be performed; but this can only take place in specialized laboratories.
Lyme routine screening test, such as immunoblot tests (immunofluorescence, ELISA, hemagglutination), is still performed by searching specific antibodies. Hemagglutination test, although representing a helpful indication toward the correct diagnosis, cannot yield sure proof of Lyme borreliosis because of the presence of false positivity in high percentage [47, 91–94].
The 2nd International Conference on Serologic Diagnosis of LD (1995) recommended a two-step approach with at first IgM and IgG ELISA test followed by Western blotting; following these recommendations, IgM blot positive results (with two or three specific bands) are only considered if occurring during the first 4 weeks of infection; IgG blots are applicable at any time of the disease, but they must be considered positive only if they have at least five out of ten specific bands .
Some studies assessed the sensitivity and specificity of these major available tests and stated that both tests were sensitive means of support for the diagnosis of LD except for erythema migrans which is diagnostic by itself [48, 91]. Positive IgM and IgG may persist for years . False-positive results are related to the cross-reactive antibodies mainly with other arthropod-derived infections and syphilis. Antibody titers to Borrelia burgdorferi decrease after antibiotic treatment [49, 95–98].
Borrelial DNA can be detected by PCR in the majority of the patients before antibiotic therapy .
Diagnostic criteria, mainly for ocular LD, are until now only exclusion criteria which are based on (1) clinical findings consistent with LD, (2) patient living in an endemic area, (3) positive serology, and (4) response to antibiotic treatment.
To obtain a correct diagnosis, the physician has to follow the indications of the Centers for Disease Control and Prevention and rely upon a specialized laboratory center provided with ELISA, Western Blot and PCR testing for Borrelia Infection. www.cdc.gov/lyme and LymeDisease.org.
5.5 Differential Diagnosis
Differential diagnosis is essential, mainly in cases of cross-reactions with syphilis and herpes viruses. As previously reported, LD is a multifaceted disorder which mimics a number of diseases, thus making the diagnosis very hard to be performed. Subjects suffering from retinal vasculitis and living in endemic LD areas have to be tested for Lyme Borreliosis .
In early stages, allergic conjunctivitis, keratoconus, meningioma, and CNS lymphoma have to be ruled out.
In late stages, paraneoplastic syndrome, multiple sclerosis, sarcoidosis, syphilis, and herpetic infections must be excluded .
Prophylactic treatment within 3 days after the infected tick bite with one dose of 200 mg doxycycline was shown to be effective in preventing the disease in 87 % of subjects [23, 101, 102].
5.6.1 Prophylaxis and Vaccination
5.6.2 Therapeutic Protocol
There is no consensus regarding which therapeutic protocol should be used in the ocular involvement of LD. Specific and early antibiotic therapy is proven to treat all LD clinical manifestations [109, 110]. Difficulties can arise in the antibiotic choice for children or pregnant or breastfeeding women [111–119].
Specific treatment is shown in Table 5.1.
Suggested antibiotic treatment for ocular Lyme disease in adults and children
2 × 100 mg/day × 2–3 weeks
3 × 500–1000 mg/day × 2 weeks
2 × 500 mg first day followed by 1 × 500 mg next 4 days (less effective than amoxicillin)
2 × 500 mg/day × 2 weeks
3 × 1–1.5 MU/day × 2 weeks
2 g/day × 2–4 weeks or other third-generation cephalosporins (i.e., cefotaxime)
20 MU/day × 2–4 weeks
3 × 25–50 mg/kg/day × 2 weeks
2 × 20 mg/kg/day first day followed by 10 mg/kg/day next 4 days (less effective than amoxicillin)
2 × 30–40 mg/kg/day × 2 weeks
3 × 0.1–0.15 MU/Kg/day × 2 weeks
50–100 mg/kg × 2–4 weeks or other third-generation cephalosporins (i.e., cefotaxime)
0.25–0.5 MU/day × 2–4 weeks
Children, pregnant, or breastfeeding women and people allergic to penicillin-derived drugs have to be given a 2–3 weeks course with erythromycin (500 mg/QID) [115–123].
Reinfections are usually treated in the same way as first infection .
It is proved that chronic persistent LB does not benefit from antibiotic therapies, even if prolonged for over 1 year and although intravenously administered [125–128].
When the nervous system is affected by Lyme disease, an aggressive intravenous antibiotic treatment is usually necessary although some patients develop persistent neurologic symptoms (multiple recurrences or long-lasting disease) .
Treatment failure is rare and sometimes bound to Borrelia persistence within the involved tissues with consequent tissue damage or postinfective autoimmune syndrome and sometimes associated with a late correct therapeutic approach related to a first wrong diagnosis in subjects with arthritis. Frequently, in facts, patients affected by systemic LD are misdiagnosed with many autoimmune diseases, i.e. multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, fibromyalgia and erroneously treated, converting a treatable infectious disease into a chronic illness .